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Metformin and Androgen Receptor-Axis-Targeted (ARAT) Agents Induce Two PARP-1-Dependent Cell Death Pathways in Androgen-Sensitive Human Prostate Cancer Cells

1
Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201, USA
2
Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
3
Baltimore VA Medical Center, Baltimore, MD 21201, USA
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Division of Endocrinology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA
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Department of Molecular Biology and Biochemistry, University of Maryland School of Medicine, Baltimore, MD 21210, USA
*
Authors to whom correspondence should be addressed.
Current address: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Academic Editor: Anderson Joseph Ryan
Cancers 2021, 13(4), 633; https://doi.org/10.3390/cancers13040633
Received: 2 January 2021 / Revised: 20 January 2021 / Accepted: 29 January 2021 / Published: 5 February 2021
(This article belongs to the Special Issue PARPs in Cancer)
In the present study, we sought to determine whether a commonly used oral drug to treat adult-onset diabetes, metformin, which has a longstanding clinical history and known safety and tolerability profile, can improve the anti-cancer effects of two well-established oral agents currently in use to treat advanced prostate cancer, abiraterone and enzalutamide. We used androgen-sensitive cell culture models of human prostate cancer to test our hypothesis. We found that metformin and the oral anti-prostate cancer agents together are more effective in inhibiting prostate cancer cell growth and inducing prostate cancer cell death than when used alone. We identified new pathways by which the enhanced anti-cancer effects occur with the combination treatments. The present work suggests that incorporating metformin with abiraterone or enzalutamide may improve treatment outcomes in hormone sensitive prostate cancer.
We explored whether the anti-prostate cancer (PC) activity of the androgen receptor-axis-targeted agents (ARATs) abiraterone and enzalutamide is enhanced by metformin. Using complementary biological and molecular approaches, we determined the associated underlying mechanisms in pre-clinical androgen-sensitive PC models. ARATs increased androgren receptors (ARs) in LNCaP and AR/ARv7 (AR variant) in VCaP cells, inhibited cell proliferation in both, and induced poly(ADP-ribose) polymerase-1 (PARP-1) cleavage and death in VCaP but not LNCaP cells. Metformin decreased AR and ARv7 expression and induced cleaved PARP-1-associated death in both cell lines. Metformin with abiraterone or enzalutamide decreased AR and ARv7 expression showed greater inhibition of cell proliferation and greater induction of cell death than single agent treatments. Combination treatments led to increased cleaved PARP-1 and enhanced PARP-1 activity manifested by increases in poly(ADP-ribose) (PAR) and nuclear accumulation of apoptosis inducing factor (AIF). Enhanced annexin V staining occurred in LNCaP cells only with metformin/ARAT combinations, but no caspase 3 recruitment occurred in either cell line. Finally, metformin and metformin/ARAT combinations increased lysosomal permeability resulting in cathepsin G-mediated PARP-1 cleavage and cell death. In conclusion, metformin enhances the efficacy of abiraterone and enzalutamide via two PARP-1-dependent, caspase 3-independent pathways, providing a rationale to evaluate these combinations in castration-sensitive PC. View Full-Text
Keywords: prostate cancer; metformin; ARAT; PARP-1; poly(ADP-ribose) (PAR); lysosome prostate cancer; metformin; ARAT; PARP-1; poly(ADP-ribose) (PAR); lysosome
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MDPI and ACS Style

Xie, Y.; Wang, L.; Khan, M.A.; Hamburger, A.W.; Guang, W.; Passaniti, A.; Munir, K.; Ross, D.D.; Dean, M.; Hussain, A. Metformin and Androgen Receptor-Axis-Targeted (ARAT) Agents Induce Two PARP-1-Dependent Cell Death Pathways in Androgen-Sensitive Human Prostate Cancer Cells. Cancers 2021, 13, 633. https://doi.org/10.3390/cancers13040633

AMA Style

Xie Y, Wang L, Khan MA, Hamburger AW, Guang W, Passaniti A, Munir K, Ross DD, Dean M, Hussain A. Metformin and Androgen Receptor-Axis-Targeted (ARAT) Agents Induce Two PARP-1-Dependent Cell Death Pathways in Androgen-Sensitive Human Prostate Cancer Cells. Cancers. 2021; 13(4):633. https://doi.org/10.3390/cancers13040633

Chicago/Turabian Style

Xie, Yi, Linbo Wang, Mohammad A. Khan, Anne W. Hamburger, Wei Guang, Antonino Passaniti, Kashif Munir, Douglas D. Ross, Michael Dean, and Arif Hussain. 2021. "Metformin and Androgen Receptor-Axis-Targeted (ARAT) Agents Induce Two PARP-1-Dependent Cell Death Pathways in Androgen-Sensitive Human Prostate Cancer Cells" Cancers 13, no. 4: 633. https://doi.org/10.3390/cancers13040633

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